RESUMEN
Zika virus (ZIKV) is a mosquito-borne Flavivirus structurally and antigenically related to Dengue virus (DENV). Zika virus has been associated with congenital anomalies and most ZIKV outbreaks have occurred in endemic areas of DENV. The present study investigated the effects of prior DENV serotype 1 (DENV1) immunity in immunocompetent female Swiss mice on gestational ZIKV infection in offspring. Physical/reflex development, locomotor activity, anxiety, visual acuity, and brain-derived neurotrophic factor (BDNF) levels were evaluated in offspring during infancy and adolescence. Anti-DENV1 and anti-ZIKV antibodies were detected in sera of the progenitors, whereas no ZIKV genomes were detected in the offspring brain. Pups from dams with only DENV1 immunity presented alterations of physical/reflex development. Pups from all infected dams exhibited time-related impairments in locomotor activity and anxiolytic-like behavior. Offspring from DENV/ZIKV-infected dams exhibited impairments in visual acuity during infancy but not during adolescence, which was consistent with morphometric analysis of the optic nerve. Pups from DENV1-, ZIKV-, and DENV/ZIKV-infected dams exhibited a decrease in BDNF levels during infancy and an increase during adolescence in distinct brain regions. In summary, we found no influence of prior DENV1 immunity on gestational ZIKV infection in offspring, with the exception of alterations of early visual parameters, and an increase in BDNF levels in the hippocampus during adolescence.
Asunto(s)
Conducta Animal , Dengue/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Complicaciones Infecciosas del Embarazo/psicología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/psicología , Animales , Encéfalo/inmunología , Encéfalo/virología , Factor Neurotrófico Derivado del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Femenino , Masculino , Aprendizaje por Laberinto , Ratones , EmbarazoRESUMEN
Reconsolidation restabilizes memory after reactivation. Previously, we reported that the hippocampus is engaged in object recognition memory reconsolidation to allow incorporation of new information into the original engram. Here we show that BDNF is sufficient for this process, and that blockade of BDNF function in dorsal CA1 impairs updating of the reactivated recognition memory trace.
Asunto(s)
Anticuerpos/farmacología , Factor Neurotrófico Derivado del Encéfalo/fisiología , Hipocampo/metabolismo , Consolidación de la Memoria/fisiología , Reconocimiento en Psicología/fisiología , Animales , Anisomicina/farmacología , Factor Neurotrófico Derivado del Encéfalo/inmunología , Hipocampo/efectos de los fármacos , Masculino , Consolidación de la Memoria/efectos de los fármacos , Inhibidores de la Síntesis de la Proteína/farmacología , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
The aim of this study was to explore the immune protective mechanism of rMOMP protein vaccine in intraocular hypertension and retinal optic nerve injury in rats. The rMOMP protein ophthalmic vaccine was prepared and quality-controlled. Sixty normal adult SD rats were randomly divided into two groups to establish a chronic ocular hypertension model and an optic nerve injury model. The model rats were vaccinated with rMOMP-CS ophthalmic vaccine. Fluorogold retrograde tracing was used to observe retinal ganglion cells, and an immunofluorescence method to determine the expression of retinal GAP43, CD3, BDNF, and GDNF. rMOMP protein ophthalmic vaccine met the requirements for medicinal use. The number of retinal ganglion cells (RGCs) of the rMOMP-CS group in the chronic ocular hypertension model was significantly higher than that of the CS group (P < 0.05). The count of RGCs of the rMOMP-CS group in the optic nerve clamping injury model was significantly higher than that of the CS group (P < 0.01). Thus, rMOMP protein ophthalmic vaccine can induce an increase in the expression of retinal neurotrophic factors, thereby exerting a protective effect on damaged retinal optic nerve.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Sistema Inmunológico/inmunología , Hipertensión Ocular/inmunología , Traumatismos del Nervio Óptico/inmunología , Vacunas/inmunología , Animales , Proteínas de la Membrana Bacteriana Externa/genética , Factor Neurotrófico Derivado del Encéfalo/inmunología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Complejo CD3/inmunología , Complejo CD3/metabolismo , Enfermedad Crónica , Femenino , Proteína GAP-43/inmunología , Proteína GAP-43/metabolismo , Factor Neurotrófico Derivado de la Línea Celular Glial/inmunología , Factor Neurotrófico Derivado de la Línea Celular Glial/metabolismo , Sistema Inmunológico/efectos de los fármacos , Masculino , Microscopía Confocal , Hipertensión Ocular/metabolismo , Hipertensión Ocular/prevención & control , Traumatismos del Nervio Óptico/metabolismo , Traumatismos del Nervio Óptico/prevención & control , Sustancias Protectoras/administración & dosificación , Distribución Aleatoria , Ratas Sprague-Dawley , Proteínas Recombinantes/inmunología , Retina/inmunología , Retina/metabolismo , Células Ganglionares de la Retina/inmunología , Células Ganglionares de la Retina/metabolismo , Estilbamidinas/metabolismo , Vacunación/métodos , Vacunas/administración & dosificaciónRESUMEN
The nitric oxide (NO)/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway is important for memory processing, but the identity of its downstream effectors as well as its actual participation in the consolidation of nonaversive declarative long-term memory (LTM) remain unknown. Here, we show that training rats in an object recognition (OR) learning task rapidly increased nitrites/nitrates (NOx) content in the CA1 region of the dorsal hippocampus while posttraining intra-CA1 microinfusion of the neuronal NO synthase (nNOS) inhibitor L-NN hindered OR LTM retention without affecting memory retrieval or other behavioral variables. The amnesic effect of L-NN was not state dependent, was mimicked by the sGC inhibitor LY83583 and the PKG inhibitor KT-5823, and reversed by coinfusion of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) and the PKG activator 8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP). SNAP did not affect the amnesic effect of LY83583 and KT-5823. Conversely, 8Br-cGMP overturned the amnesia induced by LY83583 but not that caused by KT-5823. Intra-CA1 infusion of the beta-adrenergic receptor blocker timolol right after training hindered OR LTM and, although coadministration of noradrenaline reversed the amnesia caused by L-NN, LY83583, and KT5823, the amnesic effect of timolol was unaffected by coinfusion of 8Br-cGMP or SNAP, indicating that hippocampal beta-adrenergic receptors act downstream NO/sGC/PKG signaling. We also found that posttraining intra-CA1 infusion of function-blocking anti-brain-derived neurotrophic factor (BDNF) antibodies hampered OR LTM retention, whereas OR training increased CA1 BDNF levels in a nNOS- and beta-adrenergic receptor-dependent manner. Taken together, our results demonstrate that NO/sGC/PKG signaling in the hippocampus is essential for OR memory consolidation and suggest that beta-adrenergic receptors link the activation of this pathway to BDNF expression during the consolidation of declarative memories.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Regulación de la Expresión Génica/fisiología , Receptores Adrenérgicos beta/fisiología , Reconocimiento en Psicología/fisiología , Transducción de Señal/fisiología , Antagonistas Adrenérgicos beta/farmacología , Animales , Anticuerpos/farmacología , Conducta Animal , Factor Neurotrófico Derivado del Encéfalo/inmunología , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Aprendizaje Discriminativo/fisiología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Guanilato Ciclasa/metabolismo , Masculino , Óxido Nítrico/metabolismo , Ratas , Ratas Wistar , Reconocimiento en Psicología/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Factores de Tiempo , Timolol/farmacologíaRESUMEN
Brain-derived neurotrophic factor (BDNF) is involved in many aspects of neuronal biology and hippocampal physiology. Status epilepticus (SE) is a condition in which prolonged seizures lead to neuronal degeneration. SE-induced in rodents serves as a model of Temporal Lobe Epilepsy with hippocampal sclerosis, the most frequent epilepsy in humans. We have recently described a strong correlation between TrkB decrease and p75ntr increase with neuronal degeneration (Neuroscience 154:978, 2008). In this report, we report that local, acute intra-hippocampal infusion of function-blocking antibodies against BDNF prevented both early TrkB down-regulation and neuronal degeneration after SE. Conversely, the infusion of recombinant human BDNF protein after SE greatly increased neuronal degeneration. The inhibition of BDNF mRNA translation by the infusion of antisense oligonucleotides induced a rapid decrease of BDNF protein levels, and a delayed increase. If seizures were induced at the time endogenous BDNF was decreased, SE-induced neuronal damage was prevented. On the other hand, if seizures were induced at the time endogenous BDNF was increased, SE-induced neuronal damage was exacerbated. These results indicate that under a pathological condition BDNF exacerbates neuronal injury.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Neuronas/metabolismo , Neuronas/patología , Receptor trkB/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Animales , Anticuerpos/farmacología , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/inmunología , Muerte Celular/fisiología , Modelos Animales de Enfermedad , Regulación hacia Abajo/fisiología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Agonistas Muscarínicos/toxicidad , Oligorribonucleótidos Antisentido/farmacología , Pilocarpina/toxicidad , Precursores de Proteínas/inmunología , Precursores de Proteínas/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Estado Epiléptico/inducido químicamenteRESUMEN
Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. Because brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, we examined the role of BDNF in STM and LTM formation of a hippocampal-dependent one-trial fear-motivated learning task in rats. Using a competitive RT-PCR quantitation method, we found that inhibitory avoidance training is associated with a rapid and transient increase in BDNF mRNA expression in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody into the CA, region of the dorsal hippocampus decreased extracellular signal-regulated kinase 2 (ERK2) activation and impaired STM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 activation and facilitated STM. The infusion of anti-BDNF antibody impaired LTM when given 15 min before or 1 and 4 hr after training, but not at 0 or 6 hr posttraining, indicating that two hippocampal BDNF-sensitive time windows are critical for LTM formation. At the same time points, PD098059 produced no LTM deficits. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of an inhibitory avoidance learning. Additionally, they suggest that this requirement involves ERK1/2-dependent and -independent mechanisms.